    A) Migraine, known in the past as hemicrania is one of the commoner forms of headache. It is characterised by a different clinical profile involving the brain, eye and autonomous system.
Migraine is a paroxysmal disorder, characterized by attacks of headache, often unilateral at the onset. It is further associated with anorexia and sometimes nausea and vomiting. Visual, sensory and motor or mood disturbances often accompany the above.
Migraine is estimated to affect 20–25% of population, females being more susceptible than males [Waters, W. E., Headache, 18, 53–54, (1978); Stewart, W. F. et al., Neurology, 44, S17–S23 (1994); Celentano, D. D. et al., Headache, 32, 237–38 (1992)]. In the USA alone, 23 million people are affected [Stewart, W. F. et al., JAMA, 267(1), 64–69 (1992)]. The usual age of initial onset of migraine is between an age of 5–30 years, however, the first onset of migraine attacks are commonly experienced during puberty [Diamond, S. et al., Clin. Symp., 41, 1–32 (1989)]. The prevalence of migraine increases with age and female preponderance is seen in elderly. However, there is a male preponderance in children under 12 years of age. In school going children, migraine is one of the major causes of headache. The prevalence is estimated to be one in nine children between the age group of 5–15 years [Ishaq, A. A. et al., British Medical Journal, 309, 765–769 (1994)]. Heridity also plays a role in the susceptibility of people to attacks of migraine [Ziegler, D. K. et al., Cephalgia, 2, 125–34 (1982)].
It has been reported that over 80% of migraine patients suffer from some degree of headache related disability [Stewart, W. F. et al., Cephalgia, 13 (Suppl. 12), 41–46 (1993)]. This disability would be in-terms of direct medical care cost and indirect loss of productivity. In the USA the annual loss due to these disabilities is estimated to be more than $ 17 billion [Delissvoys G. & Lazarus S. S., Neurology, 44 (6 Suppl.4), S56–S62 (1994)]. There are increasing evidences that attack of migraine often interferes with the quality of life (QOL) of an individual. Migraine is one of the causative factors for decreased school attendance or absenteeism among school going children [Ishaq, AA. et al., British Medical Journal, 309, 765–769 (1994)].    B) Several advances have been made in understanding the patho-physiological aspects of migraine. Number of theories/hypotheses have been proposed to explain the clinical features of migraine. Some of these aspects are discussed in Goodmans and Gilmans pharmacological basis of Therapeutics, 9th Int. Ed., (1996), McGraw-Hill Health Professions Division, New York, pp 486–89]. Others are:            i) Wolf (1940 & 1950) proposed the vascular theory, where vasoconstriction was identified as responsible for the aura for migraine attack and vasodilatation was responsible for the headache due to migraine. This theory has now been refuted following detailed cerebral blood flow studies [Olesen, J. et al., Headache, 22, 242–48 (1982); Lancet, 2,438–40 (1981)].        ii) Studies have demonstrated that trigeminovascular system is also the pathway for headache. The antidromic stimulation of the fifth cranial nerve C fibres and release of vasoactive neruopeptides such as substance P, calcitonin and neurokinin A produces neurogenic inflammation, which essentially consists of platelet aggregation, protein extravasation and vasculardilation, all leading to headache. The occurrence of migraine is thought of as a primary neuronal event which is initiated in the brain and followed by a wave of cortical activity called the spreading depression. These impulses are conveyed to the perivascular nerve endings where there is release of neurotransmitters, which causes vasodilatation ultimately leading to headache [Raskin, N. H., Headache, 28, 254–257 (1988); Silberstein, S. D., Neurology, 42 (Suppl 2), 6–10 (1992); Silberstein, S. D., Neurology, 42(Suppl 2), 6–10 (1992); Goadsby, P. J. et al., Ann. Neurol., 29, 91–94 (1991); Weiller C. et al., Nature Med., 1, 658–660 (1995)].        iii) The brain stem with its ascending and descending circuitry including ascending pain modulating projections from mid brain have also been shown to be an important site responsible for the persistence of the clinical features of migraine. An interest has recently been generated in the role of serotonin in the pathogenesis of migraine. Serotonin is a biogenic amine widely distributed throughout the body. Seven classes of serotonin receptors, 5-HT1 to 5HT7 have already been identified. The changes in the serotonergic brain stem can alter cranial circulation and trigger vascular phase to cause headache. This neurovascular reaction not only produces constriction or dilation of intracranial and extracranial arteries but also activates the above nociceptive trigeminal vascular system [Silberstein, S. D., Headache, 34,408–17 (1994); 1994; Moskowitz, M. A., Ann. Neurol, 16, 157–68 (1984)].        iv) The adverse effects, such as nausea, vomiting and reduced gastro-intestinal motility associated with migraine has been suggested as involving dopaminergic hyper activity [Peroutka, S. J., Neurology, 49(5), 650–656 (1997)]. However, in spite of all the above advances, the pathogenesis of migraine remains relatively unknown today.            C) Migraine, which could be moderate or severe lasts from 4 to 72 hours. The common problems associated with the attack are nausea, vomiting, forcing the persons to seek the comforts of darkness. An aura is experienced by migraineurs, which could vary from visual disturbances, partial loss of vision and tingling sensation. The International Headache Society (IHS) has proposed a new classification for headache disorders. Migraine without aura is termed as “Common Migraine” and that with aura termed as “Classic Migraine” [Headache Classification Committee of 10 HS Cephalgia, 8(Suppl.7), 1–96 (1988)].    D) The current methods of treatment of migraine essentially consists of:
Abortive (acute) treatment and
Long term prophylactic therapy.
In addition, non-pharmacological measures such as educating the patient on various aspects of migraine; ensuring that the patient's intake of food is timely; encouraging the patient to avoid tobacco, caffeinated beverages, alcohol, chocolates, food containing sodium glutamate and nitrites are also employed as part of the treatment.
Abortive (Acute) Treatment of Migraine:
This treatment [Welch, K. M. A, New. Engl. J. Med., 329, 1476–83 (1993)] aims to terminate or decrease the attack of migraine. This is achieved through administration of:                (i) Simple analgesics such as acetyl salicylic acid [Ross, L. L., et al., Cephalgia, 2, 71–76 (1982)] and acetaminophen [Peters, B. H. et al., Am. J. Med., 74, 36–42 (1983)]. These are limited for the treatment of mild to moderate migraine attacks only. It is important that the analgesics be given early in the attack. These could be combined with anti-emetics, which, however, should be used cautiously.        
However, over-usage of this class of drugs are associated with rebound headache [Mathew, N. T., Headache 30, 634–38 (1990)].                (ii) Non Steroidal Anti-Inflammatory Agents (NSAIDs) such as naproxen sodium [Nestvold, K. et al., Cephalgia, 5, 115–119 (1985)], ibuprofen [Havanka-Kanniainen, H., Headache, 29 507–09 (1989)]; ketorolac [Klapper, J. A. et al., Headache, 31, 523–524 (1991)] and indomethacin [Welch, K. M. A, N. Engl. J. Med., 329, 1476–83 (1993)] find use a first line therapy for treatment of mild to moderate attacks. Combination of NSAIDs with ergotamine tartrate or the anti-emetic compound, viz. metoclopramide is also employed for the treatment [Saadah H. A., Headache, 32, 143-146: 24 (1992)].        
These drugs, although superior to placebo in relieving the pain, however are associated with potential side effects such as nausea, abdominal pain, diarrhoea, light headedness, somnolence, fluid retention and nephrotoxicity.                (iii) Drugs belonging to the Ergot family are widely employed. Ergotamine tartrate, is the drug of choice because of its vasoconstrictive effects. It is effective in moderate to severe migraine attacks that fail to respond to simple or combination of analgesics [Quality Standards Subcommittee of American Academy of Neurology, Neurology, 45, 585–87 (1995)]. It has to be taken early during the attack to have better effect. Since it is poorly absorbed and the bioavailability is low on oral administration, a rectal dosage form is widely used for symptomatic treatment [Perrin, V. L., Clinic Pharmacokinet., 10, 334–352 (1985); Sander, S. W., Eur. J. Clin Pharmacol., 30, 331–34 (1986).        
However, there is relatively high incidence of side effects, which range from 17–41% over that observed on use of NSAIDs. Ergotamine actually exacerbates nausea and vomiting. It is contraindicated in hypertension, ischaemic heart diseases, peripheral vascular disease, hepatic & renal insufficiency and pregnancy [Hart, C., Modern Drug Discovery, 20–31 (March/April 1999)]. It cannot be taken more than two days a week or more than 10 mg per week. Further side effects such as drowsiness, tiredness or fatigue and rebound headache add to the limitations of this therapy [Silberstein, S. D., Headache, 37(Suppl.1), S15–S25(1997); Meyler, W. J., Cephalgia, 16, 5–10(1996)].
Another ergot derivative, viz. dihydoergotamine (DHE), on the other hand is very effective for the treatment of migraine [Hortone, B. T. et al., “A new product in the treatment of migraine: a preliminary report, Mayo Clin. Proc., 20, 241–48 (1945)]. It could be administrated parenterally as well as through nasal route as a spray formulation. DHE is reported to have less side effects than ergotamine and acts faster [Callaham, M. et al., Headache, 26, 168–71 (1986); Winner, P. et al., Headache, 33, 417–75 (1993)]. It is normally administrated in combination with metaclopramide [Raskin, N. H., Neurology, 36, 995–97 (1986)].
However, DHA is not prescribed widely for the treatment of migraine, for reasons unknown                (iv) The use of “triptans”, especially sumatriptan is currently used for abortive treatment of migraine [Peroutka, S. J., Headache, 30(Suppl. 1) 4–16 (1990); Mathew, N. T., Neurologic Clinics, L5(1), 61–83 (1997)]. These class of compounds are 5-HT1 receptor antagonists which can be given orally [Eur. Neurol., 31, 306–13 (1991)] or subcutaneously [Cady, R. K. et al., JAMA, 265, 2831–35 (1991); Subcutaneous Sumatriptan International Study Group, New Engl. J. Med., 325, 316–21 (1991)]. Sumatriptan is quick in action and provides 70% relief to migraine attacks in one hour compared to placebo (less than 27%). The efficacy of oral and subcutaneous administration of sumatriptan are similar, however, the onset of action of the former mode is slower than the latter.        
Although, sumatriptan is effective during the attack of migraine, it is not beneficial for preventing the onset of migraine with aura. [Goadsby, P. J. et al., Lancet, 338, 782–83 (1991); Gross, M. L. et al., Headache, 34 (10), 559–563 (1994); Bates, D. et al., Neurology, 44, 1587–92 (1994)]. Moreover, side effects such as sensation of heaviness or tightness in the chest, chest pain, pain in the throat, tingling sensation in the head or limbs, nausea and local tingling at the site of injection associated with sumatriptan are limiting factors [Subcutaneous Sumatriptan International Study Group, New Engl. J. Med., 325,316–21 (1991) Simmons, V. E. et al., Rev. Contemp. Pharmacother., 5, 319–28 (1994)]. It is also recommended that Sumaptriptan should not be administered to post menopausal women, men older than 40 years, patients with diabetes, smokers, and patients with vascular risk factors such as hypertension, hypercholesterolaemia, obesity and coronary artery disease [Hills, W. S. et al., Lancet, 341, 1564–65 (1993)]. In addition, sumatriptan cannot be administrated to patients within 24 hours of administration of ergotamine or dehydroergotamine [Kulbacka, R. T., Am. Pharm., NS 34, 3444 (1994); Diamond, S., Neurology, 45, 1039–40 (1995)]. Moreover, its concurrent administration with a monoamine oxidase (MAO) inhibitor has been considered a contraindication [Diamond, S., Neurology, 45,1039–40 (1995)].
Other triptans, viz. zolimtriptan, naratriptan and rizatriptan, are also used for the treatment of migraine. Many more are under various stages of clinical trials, which aim to bring about improvements over sumatriptan by providing shorter tmax, longer half life and good oral bioavailability, better CNS penetration and reduced cardiac effects.
The clinical study data, however reveal that hardly much improvement is achieved. Moreover, the overall efficacy rates of “triptans” is only about 65% on oral administration [Lipton, R. B., “The triptans and beyond”. In Program for the 1998 American Association for the Study of Headache, Scottdale Symposium; AASH: Scottdale, Ariz. 1998, addendum to agenda].
Prophylactic Treatment of Migraine:
This treatment aims to bring about a reduction in the frequency and severity of migraine attacks. Prophylactic treatment is given if the attack of migraine occurs 2 to 3 times a month [Stewart, W. F. et al., JAMA, 267, 64–69 (1992)]; whenever the single attack lasts for more than 2448 hours [Lipton, R. B. et al., Neurology, 43, S6-S 10 (1993); if attacks are severe [Strang, P. E., et al, Neurology, 44 S47–S55, (1994)]; inadequate relief obtained or serious side effects produced on abortive treatment [Raskin, N. H., Headache, 28, 254–57 (1988)] or if the patient is unable to cope psychologically [Osterhaus, J. T. et al., Pharmaco-economic, 2, 67–76 (1992)] with the trauma and disabilities associated with the attack [Diener, H. C., Rev. Contemp Pharmacother, 5, 271-284, (1994)].
Although, several abortive agents have been developed and are in use unfortunately, the number of agents for prophylactic treatment of migraine is not large. The class of drugs that have been clinically studied and indicated for this purpose are summarized below:                (i) Calcium channel blockers, such as flunarizine and verapamil. Although they bring about a reduction in the frequency of attack, they suffer from shortcomings such as slow onset of action, longer period of administration and contraindications for patients suffering from hypotension, congestive heart failure, arrhythmia's sick sinus syndrome, arterial fibrillation and flutter. One of the major side effects is constipation [Welch, K. M. A., New Engl. J. Med., 329 1476–83 (1993); Fullerton, T.,J. Pharmacy Pract., 6, 253-270 (1993)].        (ii) Although, Beta blockers such as proponolol, metoprolol, nadolol, atenolol and timolol, are effective in decreasing the frequency of attack [Stensrud, P., et al., Headache, 20, 204–207, (1980); Kangasniemi, P. et al., Cephalgia, 4, 91–96 (1984); Ryan, R. E. Sr. et al., Headache, 23, 26–31 (1983); Diamond, S. et al., Headache, 16, 24–27 (1976); Nadelman, J. W. et al., Headache, 26, 175–82 (1986)], their role in achieving prophylaxis is not clear, ie. whether it is through catecholaminergic system or through serotinin 5-HT2 receptors. Moreover, these compounds are contraindicated in patients suffering from insulin dependent diabetes, asthma, chronic obstructive pulmonary, heart block or failure, peripheral vascular disease, Raynaud phenomenon and pregnancy. The sudden and abrupt withdrawal of the beta blocker may cause rebound headache and other side effects such as lethargy, depression, impotence and loss of hair.        (iii) Serotonin 5-HT2 receptor antagonists such as methysergide and pizotyline are employed as prophylactic agents for the treatment of migraine. Methysergide, an ergot derivative is effective in cases where the attacks are severe, have high recurrence and do not respond to other medication [Curran, D. A. et al., J. Neurol. Neurosurg. Psychiatry, 27,463–69 (1964); Pederson, E. & Mollerice, Clin. Pharmacol. Ther., 4, 520–26 (1966); Welch. K. M. A., New Engl. J. Med., 329, 1476–83 (1993)]. Pizotyline in addition to providing relief for migraine possesses antihistaminic and anticholenergic properties.        
However, side effects, such as nausea, muscle cramps, aching, claudication, weight gain and hallucinations and other complications such as idiosyncratic retroperitoneal fibrosis associated with methysergide treatment are major concerns. In addition, methysergide is contraindicated in patients suffering from hypertension; cardiac lung, liver, kidney and collagen diseases; thrombophlebitis, peptic ulcer and pregnancy [Lance, J. W. et al., Med. J. Aust., 2(22), 909–14 (1965); Seymour, R., Med. J Aust., 1, 59–60 (1968)]. Moreover, the treatment with methysergide once started should be continued for a longer period of time (4–6 months) and should not be stopped abruptly. Use of Pizotyline is also associated with side effects such as weight gain and fatigue [Capildeo, R. & Rose F. C., Headache, 22, 272–75 (1982); Lawrence, E. R. et al., Headache, 17, 109–12 (1977); Speight, T. M. et al., Drugs, 3, 159–203 (1972)].                (iv) Tricyclic anti-depressants, like amytryptiline and nortryptiline are given when the attack is aggrevated by tension, depression or insomnia. However, these drugs produce drowsiness; anti-cholenergic effects such as dizziness, drying of mouth, blurred vision, urinary retention and cardiac arrhythmia's and in some cases weight gain. These are contraindicated in patients suffering from hypotension, glaucoma and seizures. Moreover, these drugs are to be used cautiously in elderly patients and not to be used in combination with monoamine oxidase inhibitors [Goodman and Gilman's Pharmacological basis of therapeutics, 9th Ed., Int. Ed., (1996) McGraw Hill Health Profession Division, New York, PP 498].        (v) Monoamino oxidase inhibitors such as phenelzine and isocarboxazid are given only in cases where the headaches are refractory to standard treatment. These drugs have the ability to increase the levels of endogenous 5-HT and thereby useful in migraine prophylaxis [Goodmans and Gilman's Pharmacological basis of therapeutics, 9th Ed., 1st Ed. (1996) McGraw Hill Health Profession Division, New York, 1996, pp 499]. However, side effects such as nausea, orthostatic hypotension and insomnia limit their use. Moreover, phenelzine should not be given when the patient has taken nasal decongestants.        vi) Anti-epileptic drugs such as sodium valproate, valproic acid and divalprox sodium are effective in cases where migraine attacks are associated with seizures, mania or anxiety [Jensen R., et al., Neurology, 44, 647–65 (1994); Mathew, N. T. et al., Arch Neurol., 52, 281–86 (1995)]. However, the adverse side effects such as nausea, hepatotoxicity, alopecia, tremor and weight gain and other complications as these drugs affect hemostatis and coagulation, limit their use [Siberstein, S. D., Headache, 36, 239–42 (1996) and 36, 547–55 (1996)].        vii) NSAIDs are also used for intermittent prophylaxis of migraine. However, potential gastrointestinal and renal complications limit their use.        
To summarise, the methods employed in the prior art discussed above (both abortive and prophylactic) for treatment of migraine suffer from one or more of the following shortcomings, which limit their use. These are:                a. Most of the methods are associated with serious side effects, such as nausea, vomiting, seizures, blurred vision, hepatotoxicity, hypotension, insomnia, lethargy, depression, impotence, loss of hair and weight gain, to mention a few.        b. Most of the drugs used for the treatment are contraindicated in patients suffering from hypertension, diabetes, asthma, heart block or failure, peripheral vascular disease, pregnancy, Raynaud phenomenon, lung diseases, diseases of the collagen and other diseases.        c. They cause other complications such as hemostatis and coagulation.        d. Not safe and effective.        e. Can be administrated only for a restricted period of time and cannot be stopped abruptly.        f. Lack of selectivity.        g. Affects the quality of life (QOL) of the migraineurs.        
It is also known that Sapindus trifoliatus, known as Ritha or Arishtha belongs to the family of Sapindaceae. The fruit of the plant is used therapeutically as a tonic, purgative, emetic and expectorant [Nadkarni, M. K., The Indian Materia Medica, Vol I, 2nd Ed., 1982, pp1102–03, published by Bombay Popular Prakashan, Bombay, India]. It also possesses anti-inflammatory and analgesic actions [Pharmacological investigations of certain medicinal plants and compound formulations used in ayurveda and siddha, (1996) published by CCRAS, New Delhi, India, pp 22–25]. It is also used as a spermicidal; in treatment of piles, hysteria and epilepsy and as well as for anti-implantation.
The pericarp of the fruit of the plant, which constitutes 62% of the fruit, consists of glucose (10%), and saponins(11.5%). The saponins present in the fruit on acidic hydrolysis give, hederginin, D-glucose, L-rhamnose and D-xylose [The Wealth of India, Vol IX (1998), pp 227–29, CSIR Publication, New Delhi, India].
Sapindus trifoliatus is pungent and bitter in taste. It has emetic actions ie. it causes nausea and vomiting. It also causes irritation of gastric mucosa, when administrated orally [Sharma, P. V., Dravyagunavignan (Hindi Commentary), VIIIth Ed., 1986, PP 384–86, Chaukambha Bharati Publication, Varanasi, India; Pharmacological investigations of certain medicinal plants and compound formulations used in Ayurveda and Siddha (1996), published by CCRAS, New Delhi, India, pp 22–25].
It is also known that Emblica officinalis, known as Amalaki belongs to the family of Euphorbiaceae. The fruit, leaves, bark and flowers of the plant have therapeutic value. The fruit is a rich source of Vitamin C and in addition contains tannins and other chemical constituents.
The dried fruit of Emblica officinalis is used for the treatment of peptic ulcer, dyspepsia, aging, general debility and hair loss [Nadkarni, M. K., The Indian Materia Medica, Vol. I, 2nd Editon (1982), Published by Bombay Popular Prakshan, Bombay, India, pp. 480 & 481; Indian Herbal Pharmacopoeia, Vol. II, 1999, A joint publication of RRL, Jammu & IDMA, Mumbai, India, pp. 50–57; Sharma, P. V., Dravyagunavignan (Hindi Commentary), VIIIth Edition (1986), Publication of Chaukambha Bharati, Varanasi, India, pp. 758–760]. It also finds use as a refrigerant and carminative. It also known to produce cooling and soothing effects.
Administration of Sapindus trifoliatus through nasal route is indicated for treatment of hemicrania [Nadkarni, M. K., The Indian Materia Medica, Vol I, 2 nd Ed., 1982, pp. 1102–03, published by Bombay Popular Prakashan, Bombay, India]. The therapy generally practiced consists of preparing an aqueous solution of the active ingredient and administrating the same nasally. There are no documented reports available which describe the concentration of the active ingredient, the dosage required and duration of treatment. Moreover, it is not clear whether this formulation is used as a curative or as a prophylactic. In addition, the formulated solution needs to be prepared fresh all the time, as it has no appreciable shelf life or stability. Over and above all of these, Ritha is a potential irritant and causes damage and severe irritation of the nasal mucosa, when administrated nasally. These factors severly limit the use of Ritha alone for treatment of migraine.
Even though, several combinations of Sapindus trifoliatus with ingredients of other plant species are known, there are however, no mention of any prevailing combination of Sapindus trifoliatus with Emblica officinalis [Herbal Drugs Industry: a Practical Approach to Industrial Pharmacognosy, R. D. Chaudhri Ed., Eastern Publishers, New Delhi, India, 1996].
It would thus be evident from the above that there is no reported use of Sapindus trifoliatus with Emblica officianalis in treatment of migraine. Moreover, the only known use of aqueous extracts of Sapindus trifoliatus is found to be disadvantageous as the same was accompanied with severe damage and/or irritation of the nasal mucosa membrane which made it administration complex and difficult.
Thus, a need exists for a formulation for treatment of migraine which would improve the quality of life (QOL) of migraineurs and which moreover, would minimize/eliminate the shortcomings associated with the therapies currently employed.